T-cells transmit signals received from antigen-presenting cells via T-cell receptors (TCRs) present on surfaces thereof to sub-effectors (effector T-cells) by the activation of a variety of intracellular protein kinases such as Janus kinases (JAKs). In this process, T-cells secrete various interleukins (ILs) or interferon-γ (IFN) to activate various white blood cells and also B-cells. Typical protein kinases involved in signaling in T-cells are four JAK isozymes, i.e., JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2), which will be collectively referred to as “Janus kinase” or “JAK” hereinafter.
JAKs have been widely studied as a target for treatment of autoimmune and/or inflammatory diseases. JAK inhibitors have been reported to be useful for the treatment of general symptoms of autoimmune diseases; immune system dysfunctions; viral diseases; and cancers, for example rheumatoid arthritis, psoriasis, atopic dermatitis, lupus, multiple sclerosis, type I diabetes, diabetic complications, asthma, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, cancer, leukemia, and organ transplantation or xenograft rejection (Immunol. Rev., 2008, 223(1), 132-142; Proc. Natl. Acad. Sci. U.S.A, 1995, 92(19), 8724-8728; Science, 1995, 270(5237), 800-802; Trends Pharmacol. Sci., 2004, 25(11), 558-562).
Many pharmaceutical companies have competitively studied and developed JAK3 inhibitors with the expectation of developing therapeutic agents for autoimmune diseases such as rheumatoid arthritis (RA) with selective inhibitory activity against JAK3 among JAKs. As a result, recently Pfizer's Xeljanz® (tofacitinib) has received FDA approval as a therapeutic agent for rheumatoid arthritis. However, tofacitinib thought to have selective inhibitory activity against JAK3 at the earlier stage of development has now been identified as a pan-JAK inhibitor having general inhibitory activity against the JAK kinase family, raising an ongoing controversial issue regarding that inhibitory activity against which particular JAK isozyme is the most important factor in the efficacy of a therapeutic agent for rheumatoid arthritis.
To sum up the results of a series of recent studies (Cell, 1998, 93(3), 373-383; Immunity, 2000, 13(4), 561-571; Cell, 1998, 93(3), 385-395; Lancet, 2008, 371(9617), 987-997; Chem. Biol., 2011, 18(3), 314-323), it was found that the JAK kinase that is crucial in signaling by T-cell receptors is JAK1, and JAK3 merely plays a limited auxiliary role. Accordingly, in the field of therapeutic agents for autoimmune diseases and/or inflammatory diseases, development of JAK inhibitors is focused on JAK1, not on JAK3, and substances having selective inhibitory activity against JAK1 are being reported one after another (J. Med. Chem., 2012, 55(12), 5901-5921; J. Med. Chem., 2012, 55(13), 6176-6193).
Tofacitinib, which has been identified as a pan-JAK inhibitor, was reported to have side effects, including headache, nausea, diarrhea, infection due to decreased immunity, hyperlipidemia, nasopharyngitis, increased alanine transaminase (ALT) and aspartate transaminase (AST), severe anemia, and neutropenia (Mod. Rheumatol., 2013, 23(3), 415-424). On the contrary, filgotinib as a JAK1 selective inhibitor was reported not to have such side effects of tofacitinib (Arthritis Rheum., 2012, 64 (Suppl. 10), 2489). As a result of clinical studies on various drugs known as JAK inhibitors, filgotinib and INCB-039110, as selective JAK1 inhibitors, were reported to have a significantly higher therapeutic limit than other JAK isozyme inhibitors or non-selective inhibitors (Expert Opin. Investig. Drugs, 2014, 23(8), 1067-1077).
A selective inhibitor of JAK1 is effective in the treatment of rheumatoid arthritis. Inactivation of JAK2 may induce anemia in animal models since JAK2 is essential in the erythropoietin (EPO) signaling pathway essential for red blood cell production. Accordingly, compounds having a higher enzymatic inhibition rate of JAK1 with respect to JAK2 may exhibit a relatively broad therapeutic index in JAK2-dependent anemia. Therefore, a selective inhibitor of JAK1 over JAK2 is likely to be effective as a therapeutic agent having reduced side effects for rheumatoid arthritis and other immune diseases (J. Med. Chem., 2012, 55(13), 6176-6193).
Patent document 1 discloses a wide range of compounds as JAK inhibitors represented by the following formula.

Patent document 1 discloses an assay method of inhibitory activity against JAK1, JAK2, and JAK3, but does not provide any data of a compound represented by the above formula or any comment on the selective inhibitory activity against JAK1.
Patent document 2 discloses that a compound represented by the following formula has inhibitory activity against JAK3, and an assay method of inhibitory activity against JAK3, but does not provide any data of the compound or any comment on the selective inhibitory activity against JAK1.

Patent document 2 also discloses 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amino]-piperidine-1-yl}-3-oxo-propionitrile, which corresponds to tofacitinib, the above-described FDA-approved drug.